Project Summary Streptococcus sanguinis is a common pathogen in endocarditis and a pioneer colonizer of human teeth. In heart tissues, S. sanguinis can cause infective endocarditis, but in the mouth, S. sanguinis is considered a benign or even a beneficial bacterium because the presence of S. sanguinis delays caries caused by S. mutans. A putative global regulator, Mgs, was identified in the recently completed S. sanguinis genome. Genomic analysis has revealed that the Mgs coding gene is a horizontally transferred gene. Real-time quantitative PCR experiments suggest that Mgs regulates several putativevirulence genes. The hypothesis is that Mgs is atranscriptionregulator involved in virulence gene expression in S. sanguinis. The objective of this application is to understand the mechanism of Mgs-mediated gene regulation in endocarditis and its effects on S. sanguinis in the oral community. We propose (1) to identify Mgs-regulated genes;(2) to identify Mgs DNA-binding sites and its binding domains; (3) to identify relationships among Mgs regulated proteins in silico;and (4) to identify Mgs regulated protein expressions and functions. These analyses will improve our understanding at the molecular level of this regulator and identify new targets for development of strategies, such as chemo- or immuno-therapy, against streptococcal endocarditis. Project Narrative Streptococcus sanguinis is a common pathogen in endocarditis and a pioneer colonizer of human teeth. Endocarditis is a serious, often fatal, infection of the heart. We have compared the S. sanguinis genome with other streptococcal genomes and identified a global regulator, Mgs. We propose to examine Mgs regulation, its DNA binding site, and its function in endocarditis for developing chemotherapeutic or immunotherapeutic strategies against streptococcal endocarditis.